Composition and methods employing it for the treatment of 5-HT-mediated disorders

ABSTRACT

The invention relates to a composition comprising a first component (a) which is (R)-3N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b) which is 1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile, as the racemate or an enantiomer thereof, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof The invention further concerns the preparation of the composition, pharmaceutical formulations containing said composition, and a method of treatment of affective disorders such as mood disorders and anxiety disorders with said composition, as well as a kit containing said composition.

This application is a continuation-in-part of application Ser. No.08/640,896, filed May 9, 1996, now U.S. Pat. No. 5,962,514 which is a371 of International application PCT/SE96/00526, filed Apr. 23, 1996.

FIELD OF THE INVENTION

The present invention relates to a composition which comprises a firstcomponent (a) which is (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate (NAD 299) and a second component(b) which is1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonit as theracemate or an enantiomer thereof, in the form of the free base, or apharmaceutically acceptable salt and/or solvate thereof The presentinvention also relates to a process for the preparation of the inventivecomposition, pharmaceutical formulations containing said composition andto the use of said composition either by concomitant administration orby separate administration as an improvement of the treatment ofaffective disorders such as depression, anxiety, obsessive compulsivedisorder (OCD), etc.

1. Background of the Invention

Today, it is generally considered that antidepressants take 2-4 weeks toreach full clinical effect. In contrast, the side effects occurimmediately. Thus, slow onset of action of antidepressants leads to avulnerable period for patients in which they experience the sideeffects, but not the therapeutic effects of drugs. There is often aheavy burden on the treating physician to persuade the patient tocontinue with the treatment during this period. Furthermore, in suicidalpatients, as the onset of action is gradual, initiative may be regainedwithout the experiencing of full reversal of symptoms, leaving a windowof risk for suicide and a frequent requirement for hospitalization. Anantidepressant with fast onset of action would not only be beneficialdue to the faster symptom reduction, but would also be more acceptableto patients and physicians and reduce the need for, and duration of,hospitalization. The same long period to reach full clinical effect hasbeen shown in the treatment of other affective disorders such as anxietyand OCD.

2. Prior Art

In WO 96/33710 is disclosed that the compound(R)-5-carbamoyl-8-fluoro-3-N,N-dicyclobutylamino-3,4-dihydro-2H-1-benzopyran,which has high affinity to 5-HT receptors and antagonizes5-HT_(1A)-mediated responses, induces a rapid improvement of depressedpatients treated with serotonin reuptake inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to a new composition comprising afirst component (a) which is the specific 5-HT_(1A) antagonist(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate and a second component (b) whichis1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof. Saidcomposition attains a faster onset of action and, consequently, providesa more efficacious treatment of patients suffering from affectivedisorders, particularly depression.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of compound NAD 299 on citalopram-induced 5-HTlevels.

DETAILED DESCRIPTION OF THE INVENTION

It has been shown in animal studies that acute administration ofselective 5-HT reuptake inhibitors (SSRIs) decreases the electricalimpulse propagation in 5-HT neurones via a negative feedback reactionprobably mediated by collateral 5-HT axons releasing 5-HT in raphenuclei. By inhibiting the somatodendritic 5-HT_(1A) autoreceptors in theraphe nuclei, the selective antagonists counteract the decrease inpropagation caused by 5-HT reuptake inhibitors. This indicates that aselective blockade of somatodendritic autoreceptor, i.e., 5-HT_(1A)antagonist, may have a clinical potential to improve the efficacy of5-HT reuptake inhibitors (SSRIs) and offer a new rationale for rapidonset of effect in the treatment of affective disorders, for instancethe antidepressant actions.

The compound(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate (NAD 299) disclosed herein isdescribed in J. Pharmacol. Exp. Ther. 283: 216-225 (1997) as a selective5-HT_(1A) receptor antagonist.

(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate possesses a high affinity to thespecific subgroup of 5-HT_(1A) receptor in the CNS and acts as anantagonist on that 5-HT_(1A) receptor, and also shows favorablebioavailability after oral administration.

1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof, is a 5-HTreuptake inhibitor (SSRI).1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile inthe racemic form is known as citalopram, which is commerciallyavailable. The enantiomer(+)-1-[3-(dimethylamino)propyl]-1-(pfluorophenyl)-5-phthalancarbonitrile,disclosed herein, is described in U.S. Pat. No. 4,943,590.

Pharmaceutically acceptable salts of1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile inthe racemic or enantiomeric forms may be hydrochlorides, hydrobromides,maleates, tartrates, acetates, oxalates, fumarates, etc. and are alsoincluded in the inventive composition. Also, solvate forms such as thehydrate and hemihydrate are included.

The composition according to the present invention may exist in onepharmaceutical formulation comprising component (a) and component (b),or in two different pharmaceutical formulations, one for component (a)and one for component (b). The pharmaceutical formulation may be in theform of tablets or capsules, powders, mixtures, solutions or othersuitable pharmaceutical formulation forms such as patches and nasalformulations.

The composition of the present invention can be prepared such thatcomponent (a) is incorporated into the same pharmaceutical formulationas component (b) by, e.g., mixing in a conventional way.

The present invention also includes a method of improving the onset oftherapeutic action by concomitant administration of a compositioncomprising(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate and1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof

A further embodiment of the present invention is a kit containing adosage unit of(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate and a dosage unit of1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof, optionallywith instructions for use.

Pharmaceutical formulations

According to the present invention the compounds in the composition willnormally be administered orally, rectally, transdermally, nasally or byinjection, in the form of pharmaceutical formulations comprising theactive ingredients in a pharmaceutically acceptable dosage form. Thedosage form may be a solid, semisolid or liquid fornulation. Usually theactive substances will constitute between 0.1 and 99% by weight of theformulation, more specifically between 0.5 and 20% by weight forformulations intended for injection and between 0.2 and 50% by weightfor formulations suitable for oral administration.

The pharmaceutical formulation comprises the active ingredients,optionally in association with adjuvants; excipients, e.g., diluents;and/or inert carriers.

To produce pharmaceutical formulations of the composition of theinvention in the form of dosage units for oral application, the selectedcompounds may be mixed with a solid excipient, e.g., lactose,saccharose, sorbitol or mannitol; starches such as potato starch, cornstarch or amylopectin; cellulose derivatives; a binder such as gelatinor polyvinylpyrrolidone; disintegrants, e.g., sodium starch glycolate,cross-linked PVP and crosscaramellose sodium; a lubricant such asmagnesium stearate, calcium stearate, polyethylene glycol, waxes,paraffin, and the like; and an antisticking agent such as talc orcolloidal silicon dioxide, and then compressed into tablets. If coatedtablets are required, the cores, prepared as described above, may becoated with a polymer known to one of skill in the art, e.g., HPMC, HCor other cellulose derivatives, or PVP, wherein the polymer is dissolvedin water or a readily volatile organic solvent or mixture of organicsolvents. Alternatively, the tablets can be coated with a concentratedsugar solution which may contain, e.g., gum arabic, gelatin, talcum,titanium dioxide, and the like. Dyestuffs may be added to these coatingsin order, for instance, to readily distinguish between tabletscontaining different active substances or different amounts of theactive compounds.

For the formulation of soft gelatin capsules, the active substances maybe admixed with, e.g., a vegetable oil or polyethylene glycol. Hardgelatin capsules may contain granules of the active substances using anyof the above mentioned excipients for tablets, e.g., lactose,saccharose, sorbitol, mannitol, starches (e.g., potato starch, cornstarch or amylopectin), cellulose derivatives, plasticizers,polyetheneglycol, waxes, lipids or gelatin. Also, liquids or semisolidsof the drug can be filled into hard gelatin capsules.

Dosage units for rectal application can be solutions or suspensions orcan be prepared in the form of suppositories comprising the activesubstances in a mixture with a neutral fatty base, or gelatin rectalcapsules comprising the active substances in admixture with vegetableoil or paraffin oil. Liquid formulations for oral application may be inthe form of solutions, syrups or suspensions, for example solutionscontaining from about 0.2% to about 20% by weight of the activesubstances herein described, the balance being sugar and a mixture ofethanol, water, glycerol and propylene glycol. Optionally such liquidformulations may contain coloring agents, flavoring agents, saccharinand carboxymethyl cellulose as a thickening agent or other excipientsknown to a person skilled in the art.

Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substances, preferably in a concentration of from about 0.5%to about 10% by weight. These solutions may also contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules.

Suitable daily doses of the active compounds in the composition of theinvention in therapeutic treatment of humans are about 0.01-100 mg/kgbodyweight for peroral administration and 0.001-100 mg/kg bodyweight forparenteral administration. The daily doses ofthe active ingredient(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-lbenzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate may very well differ from thedaily doses of the active ingredient1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancaibonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof, but thedoses can also be the same for both of the active ingredients.

Medical and Pharmaceutical Use

In a further aspect the present invention provides ihe use of thecomposition of a first component (a) which is(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-lbenzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate and a second component (b) whichis1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof, in thetreatment of 5-hydroxytryptamine-mediated disorders, such as affectivedisorders. Examples of affective disorders are disorders in the CNS suchas mood disorders (depression, major depressive episodes, dysthymia,seasonal affective disorder, depressive phases of bipolar disorder);anxiety disorders (obsessive compulsive disorder, panic disorderwith/without agoraphobia, social phobia, specific phobia, generalizedanxiety disorder, posttraumatic stress disorder); personality disorders(disorders of impulse control, trichotellomania); and sleep disorders.

Other disorders in the CNS such as eating disorders (obesity, anorexia,bulimia), premenstrual syndrome, sexual disturbances, alcoholism,tobacco abuse, autism, attention deficit, hyperactivity disorder,migraine, memory disorders (age-associated memory impairment, presenileand senile dementia such as Alzheimer's disease), pathologicalaggression, schizophrenia, endocrine disorders (e.g.,hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease,thermoregulatory disorders, pain and hypertension may also be treatedwith the combination described herein.

Examples of other hydroxytryptamine-mediated disorders are urinaryincontinence, vasospasm and growth control of tumors (e.g., lungcarcinoma) and it may be possible to treat those with the combinationdescribed herein as well.

Pharmacology

Potentiation of the 5-HT_(1A) autoreceptor blocking effect of 5-HT ofcitalopram by(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate (NAD 299).

Materials and methods

Animals

The studies were carried out in male Sprague-Dawley rats (290-450 g; B&KUniversal, Sollentuna, Sweden). The animals were housed for at least 3weeks after arrival until used in the experiments.

Methods

The studies were carried out by means of intra-cerebral microdialysis inconscious rats. To assess any putative regional differences betweendorsal and median raphe-innervated 5-HT projection areas, dialysisprobes were simultaneously implanted both into the frontal cortex (FCx)and dorsal hippocampus (DH).

Microdialysis

The rats were anesthetized with a mixture of ketamine HCl (67 mg/kgintraperitoneal (IP); Ketalar®, Park-Davis) and xylazine HCl (13 mg/kgIP; Rompun®, Bayer-Leverkusen). U-shaped microdialysis probes (totaldialysis fibre length 4 mm, OD 220 μm) were stereotaxically implanted inthe frontal cortex (FCx) and dorsal hippocampus (DH); probe tips at AP+3.5, ML −3.0, DV −4.2 and −4.3, ML +2.5, DV −4.2, respectively, vs.bregma and dura surface (Paxinos, et al. in the Rat Brain in StereotaxicCoordinates, 2^(nd) Ed., Academic Press, San Diego (1996)). Themicrodialysis studies were performed in conscious animals after a 40-48h recovery period, during which they were kept individually. Food andwater were allowed ad libitum in the plastic cages subsequently used inthe experimental sessions. On the day of the experiment, the probeinlets were connected to a syringe perfusion pump (CMA/100; CMAMicrodialysis AB, Sweden), delivering artificial CSF (Hjorth, S., J.Neurochem. 60: 776-779 (1993)) at a speed of 1.3 μl/min. Twenty-mindialysate fractions were collected from the probe outlet tubing, and 20immediately analyzed for 5-HT and 5-HIAA by standard HPLC-EC methods.After the perfusion was commenced, a period of 2-3 h was allowed toestablish stable baseline dialysate levels of 5-HT prior to drugtreatment(s).

Two groups of rats were injected with citalopram (5.0 mg/kg SC) at timezero. Sixty minutes later, NaCl (control) was given to one of the groupsand NAD 299 (0.3 mg/kg SC) was given to the other. The dialysate levelsof 5-HT at the frontal cortex (FCx), expressed as percentages of thecorresponding pre-injection baseline, are shown in FIG. 1.

Results:

NAD 299 (0.3 mg/kg SC), administered 60 minutes after citalopram (5mg/kg SC), strongly potentiated the 5-HT-elevating action of citalopramvs. controls (receiving citalopram +NaCl).

Conclusions

The data presented in FIG. 1 show that(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate (NAD 299) displays potent 5HT_(1A) autoreceptor blocking properties, as evidenced by its ability toi) reverse the 5-HT release-suppressing effect of the selective5-HT_(1A) receptor agonist 8-OH-DPAT, and ii) antagonize increases inendogenous agonist (5-HT) tonus at the 5-HT_(1A) autoreceptors inducedby citalopram, thereby potentiating the citalopram-induced 5-HTelevation in forebrain areas. Through its blocking of 5-HT_(1A)autoreceptors,(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate may become clinically useful inthe treatment of 5-HT-mediated disorders, particularly mood disorders.

We claim:
 1. A composition comprising a first component (a) which is(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate and a second component (b) whichis1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof.
 2. Thecomposition according to claim 1 wherein the second component (b) is1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile inracemic form.
 3. The composition according to claim 1 wherein the secondcomponent (b) is(+)-1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile.4. A method for the treatment of 5-HT-mediated disorders, whichcomprises administering to a patient suffering therefrom the compositionaccording to any one of claims 1-3.
 5. The method according to claim 4for the treatment of affective disorders.
 6. The method according toclaim 5 for the treatment of mood disorders.
 7. The method according toclaim 6 for the treatment of depression.
 8. A method of decreasing theperiod of time before the onset of therapeutic action of component (b)according to any one of claims 1-3 in a patient in need thereof, whichcomprises concomitantly administering to the patient the compositionaccording to any one of claims 1-3.
 9. A pharmaceutical formulationwherein the active ingredients are the components in the compositionaccording to any one of claims 1-3, optionally in association withadjuvants, excipients and/or inert carriers.
 10. A pharmaceuticalformulation according to claim 9 wherein the first component (a) isconcomitantly administered with the second component (b).
 11. A processfor the preparation of the composition according to any one of claims1-3 wherein the first component (a) is incorporated into the samepharmaceutical formulation as the second component (b).
 12. A processfor the preparation of the composition according to any one of claims1-3 wherein the first component (a) is in one pharmaceutical formulationand is combined with the second component (b) in a differentpharmaceutical formulation.
 13. A kit containing a dosage unit of afirst component (a) which is(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamidehydrogen (2R,3R)-tartrate monohydrate and a dosage unit of a secondcomponent (b) which is1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile,as the racemate or an enantiomer thereof, in the form of the free base,or a pharmaceutically acceptable salt and/or solvate thereof, optionallywith instructions for use.